This research will systematically examine the effects of host iron status and iron interventions on the severity of infection with malarial parasites and/or pathogenic bacteria. We will conduct this research using robust mouse models of infection. For these studies, we selected rodent malarial species, Plasmodium berghei and P. chabaudi, which, respectively, represent a highly virulent species that is rapidly lethal and a less virulent species that tends to be resolved by acquired immunity and that more closely mimics a P. falciparum infection. These two species will enable us to examine whether differences in host iron status or iron interventions can diminish malarial parasite virulence or, alternatively, exacerbate disease and increase virulence. In addition, we will use a Salmonella typhimurium sepsis model to explore the effect of iron status and iron interventions on coinfections of a malarial parasite and a common agent of bacterial coinfection. This ferrophilic enteric species is a leading cause of bacteremia in African children with or without malaria. This project exploits the unique convergence of resources and expertise at Columbia University in New York, combining investigators with expertise in models of Plasmodium infection and iron biology. Our project, which investigates mechanisms and interventions in these model systems, encompasses three Specific Aims: (1) Test the hypothesis that dietary iron deficiency anemia increases the severity of the erythrocytic phases of P. berghei and P. chabaudi malaria and of S. typhimurium, in both separate and combined infections. (2) Test the hypothesis that oral iron supplements increase the severity of the erythrocytic stages of P. chabaudi malaria and of S. typhimurium, in both separate and combined infections, by increasing plasma nontransferrin-bound iron. (3) Test the hypothesis that supplemental iron increases the severity of the hepatic stage of P. berghei infection, both in vivo and in vitro, by enhancing proliferation within hepatocytes. These studies will provide the first systematic examination of the effect of iron interventions on malarial and bacterial infection in iron-replete and iron-deficient states and will help guide the safe and effective use of iron interventions in areas with endemic malaria. PUBLIC HEALTH RELEVANCE: These studies will provide a systematic examination of the effect of iron interventions on the severity of malarial and bacterial infection in iron-replete and iron-deficient states using well-characterized mouse models of human disease. The results will provide new evidence to help guide the safe and effective use of iron interventions in areas of endemic malaria and infectious diseases.